The field of the invention is antiviral combinations and their use for the treatment or prophylaxis of influenza in a patient.
Four antiviral drugs are currently approved by FDA to treat acute, uncomplicated influenza. The M2 inhibitors amantadine hydrochloride (SYMMETREL®) and rimantadine (FLUMADINE®) are approved for treatment and prevention of influenza A. Both amantadine and rimantadine are provided in 100 mg tablets and 50 mg/ml syrup for oral administration. The usual adult dose for both drugs is 200 mg in two divided doses per day (BID). The pediatric dose of amantadine in patients 1-9 years of age is 4.4 to 8.8 mg/kg/day, not to exceed 150 mg per day; for rimantadine, the dose is 5 mg/kg administered once per day (QD), not to exceed 150 mg per day.
The neuraminidase inhibitors zanamivir (RELENZA®) and oseltamivir phosphate (TAMIFLU®) are approved for treatment and prevention of influenza A and B. Zanamivir is provided for oral inhalation only for use with an inhalation device. The recommended dose of zanamivir for prophylaxis and treatment of influenza is 10 mg/day QD and 20 mg/day BID, respectively. Oseltamivir phosphate is available as a capsule containing 75 mg oseltamivir for oral use, and as a powder for oral suspension, which when constituted with water as directed contains 12 mg/ml oseltamivir. The recommended dose of oseltamivir for patients over 13 years old for prophylaxis and treatment of influenza is 75 mg/day QD and 150 mg BID, respectively.
Various combinations of antiviral drugs have been proposed for treatment of influenza. U.S. Pat. No. 5,866,601 discloses combining neuramimidase inhibitor compositions with antivirals (such as amantadine, rimantadine and ribavirin). In vitro and in vivo animal model studies on the effect of various dual combinations of drugs against influenza have been reported (see e.g. including combinations of ribavirin with amantadine (Wilson et al., Antimicrob Agents Chemother (1980) 17:642-648; Hayden et al., Antimicrob Agents Chemother (1980) 18:536-41; and Burlington et al., J. Antimicrob Chemother (1983) 11:7-14), rimantadine (Hayden et al., supra; Galegov et al., Experientia (1977) 33:905-906; and Madren et al., Antivir Chem Chemother (1995) 6:109-113), peramavir (Smee et al., Chemotherapy (2002) 48:88-93), and oseltamivir (Smee et al., Antiviral Chem Chemother (2006) 17:185-92); and combinations of oseltamivir with amantadine (Ilyushina et al., Antiviral Res. (2006) 70:121-31) and rimantadine (Govorkova et al., Antimicrob Agents Chemother (2004) 48:4855-4863; Galabov et al., Antivir Chem Chemother (2006) 17:251-8; and Leneva et al., Antiviral Res (2000) 48:101-15). Several of these papers reported that combinations of ribavirin and amantadine have additive to synergistic effect against influenza virus compared to treatment with the drugs singly (see e.g. Wilson et al., supra; Hayden et al., supra; and Burlington et al., supra). In some of the studies, the combination treatments are reported to have adverse results compared to the monotherapy treatments. For example, the combination of oseltamivir and rimantadine at low concentrations of each drug was reported to result in an antagonistic interaction against influenza A virus (Govorkova et al., supra). Smee et al. (2006) reported that treatment of influenza A virus-infected mice with the combination of oseltamivir plus ribavirin was no better than ribavirin used alone, and that when the treatments were initiated three to four days post-infection, the groups treated with the combination had fewer survivors than the animals treated with ribavirin alone.
Viral resistance to the M2 inhibitors rimantadine and amantadine can emerge rapidly during treatment because certain single point mutations in the M2 protein can confer resistance to both amantadine and rimantadine. In January 2006, CDC testing revealed that a high proportion of influenza A viruses circulating in the U.S. were resistant to amantadine and rimantadine, causing the CDC to recommend against the use of these drugs for the treatment and prophylaxis of Influenza (CDC Health Alert, Jan. 14, 2006). Currently, oseltamivir is considered a frontline treatment for influenza A virus. However, oseltamivir-resistant strains have been reported (de Jong et al., N Engl J. Med. (2005) 353:2667-72; Euro Surveill. (2005) 10(10):E051020.2) raising concerns that transmissible, pathogenic resistant strains could reduce the benefits of antiviral use in pandemic control (Lipsitch et al., PLoS Med (2007) January 23; 4(1):e15 [Epub ahead of print]). Further, oseltamivir treatment has been linked to serious neuropsychiatric events, especially in pediatric patients (see Prescrire Int. (2006) 15:182-3).
In view of the foregoing, one object of the invention is to provide improved therapeutics for treatment or prophylaxis of influenza, particularly pandemic influenza and/or strains of influenza that are resistant to an M2 inhibitor and/or a neuramimidase inhibitor.
Another object of the invention is to provide improved therapeutics for treatment or prophylaxis of influenza that prevent the generation of drug-resistant strains within a patient or population.
Another object of the invention is to provide improved therapeutics for treatment or prophylaxis of influenza that have significantly fewer or no adverse events or toxic effects compared to current monotherapies.